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Biomedical subjects

P Costello

Publications and source records attributed to P Costello.

At least 19 recordsLinked to original sources
PubMed2006

64 slice cardiovascular CT in the emergency department: concepts and first experiences.

PURPOSE: The purpose of this study was to evaluate contrast-enhanced electrocardiogram (ECG)-gated 64-slice computed tomography (CT) angiography of the thorax as a triage tool in patients with acute equivocal chest pain. MATERIAL AND METHODS: Technical principles and diagnostic algorithms for using a single ECG-gated 64-slice CT scan for triple rule-out of acute pulmonary embolism, aortic dissection, acute coronary syndromes and other diseases of the chest are introduced. Our experience using this test in 23 patients are reviewed and exemplary cases are illustrated. The total length of hospitalisation and charges for Emergency Department care at the time of discharge were compared with a matched control population that underwent catheter angiography for emergent cardiac workup. Statistical analyses were performed with an independent Student's t test. Mann-Whitney rank sum test was also used on variables that did not have equal variance. RESULTS: Of the 23 patients, 11 presented without pathological findings, two with extensive pulmonary embolism, two with definite coronary artery disease (CAD) but stenosis <50% and eight with significant CAD (>50% stenosis). Catheter angiography was performed in the latter group, confirming the CT findings in all cases. Nine patients without CT findings were discharged on the same day. In comparison with the control group, length of hospitalisation (p=0.009) and total hospital charges (p<0.001) were significantly reduced. CONCLUSIONS: Our initial experience shows that ECG-gated 64- slice CT angiography of the entire thorax is technically feasible and enables rapid triage of patients to determine underlying cardiac and noncardiac reasons for chest pain. This test may thus help to significantly reduce costs and length of hospitalisation. Prospective studies involving larger groups of patients are required to confirm these findings.

Adult↗
PubMed2001

Inhibition of integrin linked kinase (ILK) suppresses beta-catenin-Lef/Tcf-dependent transcription and expression of the E-cadherin repressor, snail, in APC-/- human colon carcinoma cells.

Loss of functional adenomatous polyposis coli (APC) protein results in the stabilization of cytosolic beta-catenin and activation of genes that are responsive to Lef/Tcf family transcription factors. We have recently shown that an independent cell adhesion and integrin linked kinase (ILK)-dependent pathway can also activate beta-catenin/LEF mediated gene transcription and downregulate E-cadherin expression. In addition, ILK activity and expression are elevated in adenomatous polyposis and colon carcinomas. To examine the role of this pathway in the background of APC mutations we inhibited ILK activity in APC-/- human colon carcinoma cell lines. In all cases, inhibition of ILK resulted in substantial inhibition of TCF mediated gene transcription and inhibition of transcription and expression of the TCF regulated gene, cyclin D1. Inhibition of ILK resulted in decreased nuclear beta-catenin expression, and in the inhibition of phosphorylation of GSK-3 and stimulation of its activity, leading to accelerated degradation of beta-catenin. In addition, inhibition of ILK suppressed cell growth in culture as well as growth of human colon carcinoma cells in SCID mice. Strikingly, inhibition of ILK also resulted in the transcriptional stimulation of E-cadherin expression and correlated with the inhibition of gene transcription of snail, a repressor of E-cadherin gene expression. Overexpression of ILK caused a stimulation of expression of snail, but snail expression was found not to be regulated by beta-catenin/Tcf. These data demonstrate that ILK can regulate beta-catenin/TCF and snail transcription factors by distinct pathways. We propose that inhibition of ILK may be a useful strategy in the control of progression of colon as well as other carcinomas. Oncogene (2001) 20, 133 - 140.

Adenomatous Polyposis Coli↗
PubMed2001

Disease mechanisms in psoriasis and psoriatic arthritis.

Any hypothesis that tries to explain disease mechanisms in psoriasis and psoriatic arthritis (PsA) must take into account the containment of the inflammatory process to three specific sites: the skin, synovium, and enthesis. This article reviews the recent literature that advances our understanding of disease mechanisms at these specific sites. Additional progress will be achieved by research that focuses on common pathogenic pathways at these sites, in particular when searching for foreign candidates or auto-antigens triggering the T-cell-mediated immune response.

Arthritis, Psoriatic↗
PubMed2001

Pulmonary embolism: imaging modalities--V/Q scan, spiral (helical) CT, and MRI.

Ventilation-perfusion (V/Q) imaging has been used as the screening test for pulmonary embolism (PE) for many years with diagnostic algorithms developed as a result of the Prospective Investigation of Pulmonary Embolism Diagnosis study. The primary conclusions were that high probability V/Q scans were reliable indicators for PE and normal or near-normal scans were reliable in the exclusion of PE. With the increasing availability of spiral (helical) computed tomography (CT) and many studies showing a high degree of accuracy for PE, there is much support for the replacement of V/Q by spiral CT. This article reviews the literature concerning V/Q scanning, spiral (helical) CT, and the future potential for magnetic resonance in the diagnosis of PE.

Humans↗
PubMed2001

The radiology of pulmonary cryptococcosis in a tertiary medical center.

Pulmonary cryptococcal infections occur in both immunocompetent and immunocompromised individuals, with a reported increased incidence of diffuse pulmonary disease in acquired immune deficiency syndrome (AIDS) patients. The authors observed no differences in the radiographic appearances of pulmonary cryptococcal disease between human immunodeficiency virus (HIV) patients and other immunocompromised individuals. Chest computed tomography (CT) contributes to a more comprehensive understanding of pulmonary cryptococcal infections.

AIDS-Related Opportunistic Infections↗
PubMed2001

Acute respiratory failure associated with pulmonary cryptococcosis in non-aids patients.

PURPOSE: To determine the incidence of acute respiratory failure (ARF) in non-AIDS patients with pulmonary cryptococcosis (PC). DESIGN: Retrospective cohort study. SETTING: University of Pittsburgh Medical Center, Pittsburgh, PA. SUBJECTS: All patients in whom PC without HIV infection was diagnosed between February 1989 and March 1999. RESULTS: Thirty-three patients with PC were identified, and 11 of those patients (33%) developed ARF and comprised the study group. Underlying diseases included solid-organ transplant recipients (seven patients; 64%) and other underlying medical conditions (four patients; 36%). The most common symptoms were cough, shortness of breath, and temperature elevation. Extrapulmonary involvement was seen in six patients (meningitis, four patients; peritonitis, one patient; laryngeal mass, one patient). Six of the 11 patients (55%) died. CONCLUSION: ARF may develop in one third of non-AIDS patients with PC. This clinical syndrome is associated with the dissemination to extrapulmonary sites and high mortality rates. PC should be recognized as a possible cause of respiratory failure in non-AIDS patients.

Acute Disease↗
PubMed2001

CT features of pulmonary alveolar proteinosis.

OBJECTIVE: This investigation describes the CT features of pulmonary alveolar proteinosis in a large group of patients. MATERIALS AND METHODS: A retrospective review of 139 chest CT scans (79 thick-section scans and 60 thin-section scans) from 27 patients with pathologically proven pulmonary alveolar proteinosis was performed. Two independent observers assessed the intraslice patterns and zonal distribution of disease on three CT images of each lung. The observers also graded the percentage of ground-glass opacities, air-space opacities, fibrosis, interlobular opacities, intralobular opacities, and emphysema in each slice. CT scans obtained before and after lavage related to 12 whole-lung lavage treatments on nine patients were evaluated. RESULTS: The dominant intraslice pattern was geographic, but a diffuse pattern was sometimes seen. The most common zonal pattern was uniform; a lower zone predominance was next most frequent. Ground-glass, air-space, and fibrotic opacities had a generally homogeneous craniocaudal distribution, but there was a trend toward more interlobular opacities at the lung bases (p < 0.002). Ground-glass opacities were seen on at least one scan in 100% of the patients. Interlobular opacities (85%), air-space opacities (78%), substantial fibrosis (7%), and intralobular opacities (7%) occurred less frequently. Compared with thick-section images, thin-section images showed more interlobular opacities, but no difference in ground-glass, air-space, or fibrotic disease. The proportion of lung affected by ground-glass and interlobular opacities decreased significantly (p < 0.05) after lavage. CONCLUSION: Pulmonary alveolar proteinosis does not present only with alveolar disease. The CT appearance typically combines different types of opacities with a geographic pattern and a uniform zonal distribution with variation over time.

Adult↗
PubMed2000

The integrin linked kinase (ILK) induces an invasive phenotype via AP-1 transcription factor-dependent upregulation of matrix metalloproteinase 9 (MMP-9).

Overexpression of Integrin Linked Kinase (ILK) in intestinal and mammary epithelial cells results in a highly invasive phenotype, associated with increased levels of expression of the matrix metalloproteinase MMP-9. This increase was at the transcriptional level as determined by MMP-9 promoter-CAT reporter assays. Mutations in the two AP-1 binding sites within the MMP-9 promoter completely inhibited the reporter activity. We have previously shown that ILK inhibits glycogen synthase kinase-3 (GSK-3) activity. Transient transfection of wild-type GSK-3beta in ILK-overexpressing cells decreased MMP-9 promoter activity and AP-1 activity, indicating that ILK can stimulate MMP-9 expression via GSK-3beta and AP-1 transcription factor. A small molecule inhibitor of the ILK kinase reduced the in vitro invasiveness of ILK-overexpressing cells as well as the invasiveness of several human brain tumor cell lines. Furthermore, both MMP-9 promoter and AP-1 activities were inhibited by the ILK inhibitor. Invasiveness of ILK-overexpressing cells was also reduced by inhibition of MMP-9. These data demonstrate that ILK can induce an invasive phenotype via AP-1-dependent upregulation of MMP-9.

Animals↗
PubMed2000

Integrin-linked kinase (ILK): a "hot" therapeutic target.

Integrin-mediated cell adhesion is known to regulate gene expression through the activation of transcription factors. We have recently revealed that these activations are mediated through integrin-linked kinase (ILK). ILK is an ankyrin repeat-containing serine-threonine protein kinase that can interact directly with the cytoplasmic domain of the beta1 and beta3 integrin subunits and whose kinase activity is modulated by cell-extracellular matrix interactions. We have shown that ILK overexpression results in the translocation of beta-catenin to the nucleus, which then forms a complex formation with the lymphoid enhancer binding factor 1 (LEF-1) transcription factor, subsequently activating the transcriptional activity of promoters containing LEF-1 response elements. ILK phosphorylates the glycogen synthase kinase-3 (GSK-3), which inhibits GSK-3 activity. We have demonstrated that ILK stimulates activator protein-1 transcriptional activity through GSK-3 and the subsequent regulation of the c-Jun-DNA interaction. ILK also phosphorylates protein kinase B (PKB/Akt) and stimulates its activity. We have shown that ILK is an upstream effector of the phosphatidylinositol 3-kinase-dependent regulation of PKB/Akt. ILK has been shown to phosphorylate PKB/Akt on Ser-473 in vitro and in vivo. Our results clearly indicate that ILK is a key element in the regulation of integrin signaling as well as growth factor and Wnt signaling pathways. PTEN (phosphatase and tensin homolog detected on chromosome 10) is a tumor suppressor gene located on chromosome 10q23 that encodes a protein and phospholipid phosphatase. It is now estimated that inactivation mutants of PTEN exist in 60% of all forms of solid tumors. Loss of expression or mutational inactivation of PTEN leads to the constitutive activation of PKB/Akt via enhanced phosphorylation of Thr-308 and Ser-473. We have demonstrated that the activity of ILK is constitutively elevated in PTEN mutant cells. A small molecule ILK inhibitor suppresses the phosphorylation of PKB at the Ser-473 but not the Thr-308 site in the PTEN mutant cells. These results indicate that inhibition of ILK may be of significant value in solid tumor therapy.

Animals↗
PubMed2000

Multipoint rank-order study methodology: observer issues.

RATIONALE AND OBJECTIVES: We performed a multipoint rank-order experiment to evaluate variability in observers' sensitivity to small differences in image presentation and to assess observers' performance as a function of the type and number of tasks included. METHODS: Five experienced observers were presented with four sets of chest images that had been compressed at five different levels. Each set contained six images ranging from noncompressed to approximately 60:1-compressed images. Observers were asked to review all images of each case side by side and rank-order the "quality" of each to enable determination of the presence or absence of interstitial disease and/or pneumothoraces. RESULTS: Observers varied significantly in their ability to detect very small differences among the images (P < 0.001). Those who performed well did so regardless of whether they ranked a specific abnormality in a multidisease or a single-disease setting. CONCLUSIONS: Selected observers can reliably detect very small differences among similar images. These readers could be used to confirm or rule out the need for objective observer-performance-type studies.

Humans↗
PubMed1999

Frequent loss of imprinting of PEG1/MEST in invasive breast cancer.

The human PEG1 gene is a newly identified imprinted gene on 7q32. Genetic aberrations of this chromosomal region are often detected in invasive breast carcinomas. In this study, we show monoallelic PEG1 expression in normal breast tissue, indicating the presence of a functional imprint, and more importantly, we demonstrate loss of imprinting (LOI) in all of seven informative invasive breast carcinomas. In contrast to this, in one case of atypical ductal hyperplasia (ADH) found in residual breast, imprinting was maintained. This raises the possibility that aberrant imprinting of PEG1 may be involved in the progression from hyperplasia to invasive breast cancer.

Alleles↗
PubMed1999

The SH3 domain of Bruton's tyrosine kinase displays altered ligand binding properties when auto-phosphorylated in vitro.

Btk is a member of the Tec family of protein tyrosine kinases expressed in B cells. It is stimulated following cross-linking of the B cell receptor which leads to the autophosphorylation of a specific residue in the SH3 domain, Y223. Previous work using Btk-derived fusion proteins has shown that the Btk SH3 domain binds to c-Cbl and Wiskott-Aldrich syndrome protein (WASP) in vitro. We show here that when the Btk SH3 domain fusion protein is autophosphorylated, its ability to take part in protein interactions is altered as compared to the non-phosphorylated fusion protein. Although the phosphorylated Btk SH3 domain still binds c-Cbl, it no longer binds WASP and instead acquires a high affinity for kinase-active Syk. The region of Syk responsible for this interaction is contained within its C terminus, suggesting a novel mechanism by which these proteins may interact.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1999

Role of spiral computed tomography in the diagnosis of pulmonary embolism in the emergency department.

Recently a debate has developed in the medical community as radiologists in some centers suggest the selective substitution of spiral computed tomography (CT) for ventilation-perfusion (V/Q) nuclear medicine imaging as a screening test for the diagnosis of acute pulmonary embolism. Proponents of spiral CT argue that it is more accurate than the usual practice of combining the (V/Q) scan and the physician's best clinical judgment. V/Q scans classify patients into groups according to the probability of pulmonary emboli, whereas the thrombus is visible with spiral CT. Opponents point out that large-scale patient outcome studies using spiral CT have not been completed, but such information is available for (V/Q) scans. Most clinicians are familiar with the strengths and limitations of an assessment that relies primarily on the (V/Q) scan, because this examination has been available for many years. Although spiral CT does not perform as well as pulmonary arteriography in detecting subsegmental emboli, the importance of smaller peripheral emboli is controversial. This review explores the advantages and disadvantages of investigations currently available for the diagnosis of acute pulmonary embolism from the perspective of the emergency physician, presenting the view that spiral CT is likely to have an increasingly important place in patient evaluation.

Algorithms↗